Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells

Abstract

Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4¢-diisothiocyanatostilbene-2,2¢-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis. (Cancer Sci 2011; 102: 1007-1013 M onocarboxylates, such as lactate and pyruvate, play a central role in cellular metabolism and metabolic communication between tissues.(1) In cancer cells, a steady source of metabolic energy is required to continue the uncontrolled growth and proliferation of these cells.(2) Most cancer cells rely on a high rate of aerobic glycolysis, a phenomenon termed ''the Warburg effect'', to obtain sufficient ATP in a hypoxic microenvironment.(3) As a result of the Warburg effect, lactate is abundantly synthesized from pyruvate, (4) but lactic acid induces cellular acidosis, which triggers apoptosis. To avoid apoptosis, cancer cells must transport the lactate out of the cell. On the other hand, lactate is not just a waste product: it was recently identified as a major energy fuel in tumors.(4) Lactate is transported by monocarboxylate anion transporters (MCT; also called the solute carrier family 16 [SLC16]).(1) It is known that MCT4 (SLC16A3) transports lactate out of the cell (5) and MCT1 (SLC16A1) regulates the entry of lactate into tumor cells. (4) Migration and invasion are two of the most important aspects of the malignant cancer phenotype; if they could be inhibited, the cancer prognosis would improve. Hypoxia and acidosis create a nurturing environment for tumor progression and the evolution of metastases, and invasiveness is abetted by acidosis, the result of shifting to an anaerobic glycolytic metabolism.(6) Basigin (BSG; also called EMMPRIN and CD147) is a multifunctional glycoprotein ...

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…While the migration of glucose-starved TCs depends on MCT1 expression and activity (Figure 6), CD147 is known to promote invasion, 15,36,37 so it can logically be proposed that MCT1-CD147 accumulation allows cell to escape from harsh environments. Accordingly, forced overexpression of either of the partners (resulting in the stabilization of both of them as previously reported in other systems) [13][14][15] was sufficient to promote TC migration (Figure 6f and Supplementary Figure 6C).…”

“…The contribution of MCT1 to migration was seen with glucose or serum as chemoattractants but not with lactate or glutamine used at their relevant concentrations in culture media (Supplementary Figure 6B), explaining why others in non-metabolically controlled systems failed to detect MCT1-dependent migration other than random. 37 On another hand, CD147 upregulation under glucose starvation could help survivor cells to combat excess oxidative stress before evading to better soils: in malignant melanoma cells, silencing CD147 has been shown to induce ROS production. 38 Our characterization of the molecular pathway through which mitochondria control MCT1 and CD147 revealed a key role of mitochondrial ROS.…”

Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae

“…The "Warburg effect" has been related to overexpression of hexokinase 2 (HX2) and its binding to mitochondria (Ko et al 2001;Geschwind et al 2002;Mathupala et al 2009;Pedersen 1978;Pedersen 2007). It also involves the monocarboxylate transporters MCT1 & MCT4 and the mitochondrial phosphate carrier (PIC) (Mathupala et al 2010;Izumi et al 2011;Mathupala et al 2006). However, how 3-BP selectively affects only cancer cells is not understood.…”

Intensified expressions of a monocarboxylate transporter in consistently renewing tissues of the mouse

“…It is known that most cancer cell lines express MCT1 rather than GLUTs. Eleven human lung cancer cells examined largely expressed MCT1 and MCT2, and a knockdown of these MCTs significantly reduced the migration of cancer cells (18). Our preliminary examination of human cancer also indicated that most cancers express MCT1 rather than GLUT1.…”